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Immunity or tolerance: Opposite outcomes of microchimerism from skin grafts

Nature Medicine volume 7, pages 80–87 (2001)Cite this article

Abstract

Solid organ transplants contain small numbers of leukocytes that can migrate into the host and establish long-lasting microchimerism. Although such microchimerism is often associated with graft acceptance and tolerance, it has been difficult to demonstrate a true causal link. Using skin from mutant mice deficient for leukocyte subsets, we found that donor T-cell chimerism is a 'double-edged sword' that can result in very different outcomes depending on the host's immunological maturity and the antigenic disparities involved. In immunologically mature hosts, chimerism resulted in immunity and stronger graft rejection. In immature hosts, it resulted in tolerance to the chimeric T cells, but not to graft antigens not expressed by the chimeric cells. Clinical efforts aimed at augmenting chimerism to induce tolerance must take into account the maturation state of host T cells, the type of chimerism produced by each organ and the antigenic disparities involved, lest the result be increased rejection rather than tolerance.

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Figure 1: T cells migrate out of donor skin grafts into immunodeficient recipient mice.
Figure 2: T cell-containing but not T cell-deficient skin grafts induce central tolerance.
Figure 3: Skin-graft-derived T cells but not APCs are a long-lived source of immunogenic graft antigen for CTLs in the periphery.
Figure 4: Inability of chimerism to prevent rejection of grafts mismatched for multiple minor or major histocompatibility complex antigens.
Figure 5: T-cell chimerism induces tolerance of T-cell targets in MHC class I-restricted killer cells, but some other host T-cell responses remain unaffected.

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Acknowledgements

We thank E. Bonney for assistance in thymus grafting, A. Bendelac, O. Lantz, J. Powell, A. Rosenberg, R. Schwartz and S. Gallucci for critical reading of the manuscript (and statistical analysis by O. Lantz), and members of the Ghost Lab (O. Alpan, S. Celli, S. Gallucci, K. Goldman, L. Graham, T. Kamala, R. Massey and J. Ridge) and the Laboratory of Cellular and Molecular Immunology for discussions.

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  1. Ghost Lab, Section on T-cell Tolerance and Memory, Laboratory of Cellular and Molecular Immunology, NIAID/NIH Building 4 Room 111, 9000 Rockville Pike, Bethesda, 20892-0420, Maryland, USA

    Colin C. Anderson & Polly Matzinger

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Correspondence to Colin C. Anderson.

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Anderson, C., Matzinger, P. Immunity or tolerance: Opposite outcomes of microchimerism from skin grafts. Nat Med 7, 80–87 (2001). https://doi.org/10.1038/83393

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